Angiopoietin-1 - fibrin gel matrix constructs for vessel stabilization
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1 Research Collection Doctoral Thesis Angiopoietin-1 - fibrin gel matrix constructs for vessel stabilization Author(s): Weber, Cornelia Christine Publication Date: 2004 Permanent Link: Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library
2 Diss ETH No Angiopoietin-1 - fibrin gel matrix constructs for vessel stabilization A dissertation submitted to the Swiss Federal Institute of Technology Zürich for the degree of Doctor of Natural Sciences Presented by Cornelia Christine Weber Diplom-Biotechnologe, ESBS Strasbourg born citizen of Germany Accepted on the recommendation of Prof. Dr. Jeffrey Alan Hubbell, examiner Dr. Andreas H. Zisch, co-examiner Prof. Dr. Martin Fussenegger, co-examiner Zürich, 2004
3 Summary Vascular repair and bone regeneration are important targets of biomedical research. As an alternative or adjunct therapy to surgery, great attention has been directed to towards the induction of new blood vessel growth (angiogenesis) or new bone by recombinant growth factor protein therapy. In the case of therapeutic angiogenesis, these approaches include the use of vascular endothelial growth factor (VEGF) or angiopoietin-1 (Ang1), in the case of bone repair, the use of insulin-like growth factor-1 (IGF1). Given the typically long time course of healing of diseased tissue, methods of prolonged growth factor delivery from depot devices could become critical. Moreover, dosage should be kept low and local at the compromised tissue site to prevent adverse systemic effects. Towards this aim, we have developed delivery devices for Ang1 and IGF1 that base on natural fibrin hydrogel matrix which is clinically widely applied as fibrin glue. We generated constructs of Ang1 or IGF1 that possess an aminoterminal transglutaminase factor XIII substrate domain that couples the protein to fibrin, followed by a plasmin-sensitive cleavage motif, and the protein itself. Covalent conjugation of these variant forms of Ang1 or IGF1 to the fibrin gel matrix provided retention of Ang1 or IGF1 in the fibrin matrix until their liberation by local, cell associated proteolytic activity that cleaves the matrix, or the coupling domain within the protein itself. VEGF is a potent inducer of new vessel growth. However, vessels induced by VEGF tend to be leaky and prone to regression. These effects may potentially be counteracted by the vessel stabilizing activities of Ang1 which appear to rest on the tightening of endothelial cell junctions and the increased association of endothelium with mural supporter cells in the nascent vessel wall. For that reason, recombinant Ang1 therapy has become a strategy in approaches to formation of healthy, lasting vasculature. A challenge has remained how to produce the multimeric/multidomain structure of native Ang1 in signaling competent and therapeutically relevant form: Native Ang1 possesses at its aminoterminus a domain that makes this protein prone to aggregation. In this work, the presumed need for Ang1 multimericity for function was challenged by a variant form of Ang1 that lacks the aminoterminal aggregation domain. In an initial screen, we analyzed the activity of monomeric Ang1 on developing chicken chorioallantoic membrane: Transduction of chicken tissue with lentiviral particles encoding the isolated, monomeric Ang1 fibrinogen-like domain resulted in thinning of vessels and profound reduction of vessel branching that compared the effect of full-length Ang1. This led us to explore the potential of an isolated fibrinogen-like domain of Ang1, Tp- Ang1, which couples to fibrin. We developed protocols that permit straightforward purification of Tp- Ang1 in insect cells. The functional properties of Tp- Ang1 were characterized in vitro and in vivo side by side with full-length Ang1. As expected, this monomeric form of Ang1 bound Tie2 receptor but did not induce its phosphorylation. Unexpectedly, our studies with Tp- Ang1 in soluble form or formulated in fibrin revealed that monomeric Tp- Ang1 was capable to exert multiple established effects of full-length Ang1. These included inhibition of basal endothelial permeability; the induction of endothelial cell-adhesion and subsequent integrin-mediated, mitogen-activated protein kinases signaling. In the chicken chorioallantoic assay, fibrin formulated with full- 3
4 length Ang1 or Tp- Ang1 substantially reduced vessel branching, presumably as a result of the intended vessel stabilization. Collectively, our experimental arrays indicate that monomeric forms of Ang1 are capable to elicit characteristic effects of full-length Ang1. These results add an important new aspect to angiopoietin biology by indicating that some functions of Ang1 are independent of Tie2 activation. Fibrin delivery devices releasing monomeric Tp- Ang1 alone, or in combination with vascular endothelial growth factor, could become useful in approaches to lasting revascularization. In a subsequent study, we developed a novel, factor XIII-based method for artificial clustering of proteins using as a template for multimerization a 4-arm polyethylene glycol macromer. By this method, higher order proteins could be obtained, as proven at the example of Tp- Ang1. The bioactivity of a fibrin-coupling IGF1 variant, Tp-IGF1, was assessed in vitro and in vivo. Positive results could be obtained in three animal models of bone regeneration that included the rat cranium, sheep drill hole and rabbit segmental defect model. Zusammenfassung Das therapeutisch induzierte Wachstum neuer Blutgefässe (Angiogenese) sowie die Regeneration von Knochen gehören zu den wichtigsten Feldern in der biomedizinischen Forschung. Der Hauptfokus dieser Forschung liegt in der Anwendung von proteinbasierten rekombinanten Wachstumsfaktoren als Alternative oder Ergänzung zu bisher etablierten chirurgischen Methoden. Die vielversprechendsten Wachstumsfaktoren für die therapeutische Angiogenese sind der vaskuläre endotheliale Wachstumsfaktor (VEGF) sowie Angiopoietin- 1 (Ang1), wohingegen der Insulin-ähnliche Wachstumsfaktor-1 (IGF1) eine prominente Rolle in der Knochenregeneration einnimmt. Für eine wohldosierte und nachhaltige therapeutische Anwendung unter gleichzeitiger Vermeidung von systemischen Nebenwirkungen, sollten diese Wachtumsfaktoren von einem Depot über einen ausreichenden Zeitraum in genau definierbaren Dosen am Zielort freigesetzt werden. Um diesen Anforderungen zu entsprechen, entwickelten wir ein Verfahren zur kontrollierten Freisetzung von Ang1 und IGF1 aus klinisch validierten (Fibrinkleber) Fibrin-basierten Hydrogelen. Die von uns hergestellten Ang1- oder IGF1-Varianten besitzen am Aminoende eine Substratdomäne für den Transglutaminase-Faktor XIII, welche für die Bindung des Proteins an Fibrin notwendig ist, gefolgt von einer Plasmin-empfindlichen Domäne. Die kovalente Bindung dieser neuen Ang1 und IGF1 Varianten in die Fibrinmatrix führt dazu, dass diese solange in der Matrix immobilisiert werden, bis sie durch zelluläre Proteasen lokal und dosiert freigesetzt werden, entweder durch Hydrolyse der Fibrinmatrix oder der hierfür plazierten N-terminalen Plasminschnittstelle des Wachstumsfaktors. VEGF induziert das Wachstum neuer Blutgefässe, die jedoch die Tendenz haben, permeabel zu sein oder sich wieder zurückzubilden. Diesen Effekten könnte durch die blutgefässstabilisierenden Wirkungen von Ang1 begegnet werden, das zu einer Verdichtung 4
5 von Endothelzell-Verbindungen und einer verstärkten Verbindung des Endotheliums mit den Wandzellen in der wachsenden Blutgefässwand führt. Eine auf rekombinantem Angiopoietin- 1 basierte Therapie, um ausgereifte und stabile Blutgefässe nachhaltig zu induzieren, erfordert die Herstellung einer biologisch aktiven Form dieses multimeren, stark aggregierenden und schwer zu produzierenden Wachstumsfaktors in ausreichenden Mengen in einer therapeutisch relevanten Formulierung. In dieser Arbeit überprüfen wir die mutmassliche Notwendigkeit der Multimerisierung von Ang1 für seine therapeutische Funktion durch Herstellung einer Ang1-Variante mit deletierter aminoterminalen Aggregationsdomäne. In einer anfängliche Validierung führte die lentiviral-vermittelte Expression dieser verkürzten monomeren Ang1-Variante in der embryonalen Hühner- Chorioallantoischen Membran zu dünnen Blutgefässen mit einer deutlichen Reduktion der Blutverzweigungen, was dem Effekt des nativen Ang1 entspricht. Basierend auf diesem Resultat entwickelten wir ein Protokoll für Insektenzell-basierte Expression der monomeren Ang1-Variante für die anschliessende kovalente Integration in ein Fibrinpolymer. Die funktionellen Eigenschaften von Ang1 und Tp- Ang1 wurden in vitro und in vivo untersucht. Wie erwartet konnte die monomere Form von Ang1 den Tie2-Rezeptor binden, aber nicht dessen Phosphorylierung hervorrufen. Ueberraschenderweise zeigten unsere Untersuchungen, dass Tp- Ang1 in löslicher Form oder in der Fibrinmatrix in der Lage war, mehrere Effekte von Ang1 hervorzurufen, und zwar Hemmung der basalen Endothelzellpermeabilität, Induktion der Adhäsion von Endothelzellen und die daraus folgende integrin-vermittelte Mitogen-aktivierte Proteinkinase Signaltransduktion. In Experimenten mit chorioallantoischer Hühnermembran führte Fibrin mit gekoppeltem Ang1 oder Tp- Ang1 zu deutlich reduzierten Blutgefässverzweigungen, vermutlich als Folge der induzierten Blutgefässstabilisierung. Insgesamt weisen unsere Experimente darauf hin, dass monomere Formen von Ang1 in der Lage sind, charakteristische Effekte von Ang1 zu induzieren. Diese Ergebnisse sind wichtige neue Aspekte in der Biologie des Angiopoietins, da sie andeuten, dass mehrere Funktionen von Ang1 unabhängig von Tie2-Aktivierung sein könnten. Somit könnte sich eine Matrix aus Fibrin, die monomeres Tp- Ang1 alleine oder in Kombination mit VEGF freisetzt, als wertvoll für die therapeutische Bildung dauerhafter Blutgefässe erweisen. In einer weiteren Studie entwickelten wir eine neue, Faktor XIII-basierte Methode für die künstliche Multimerisierung von Proteinen, die als Gerüst ein 4-armiges Polyethylenglykol- Makromer verwendet. Mit Hilfe dieser Methode könnten Multimere höherer Ordnung gebildet werden, wie am Beispiel des Tp- Ang1 gezeigt wird. Die biologische Aktivität einer Fibrin-inkorporierenden IGF1-Variante, Tp-IGF1, wurde in vitro und in vivo untersucht. Positive Ergebnisse wurden in mehreren Tiermodellen in der Knochenregeneration erzielt, wobei wir ein Schädelmodell in Ratten, ein Bohrlochmodell im Schaf und ein Ulnaknochenmodell im Kaninchen verwendeten. 5
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